This application addresses broad Challenge Area (08): Genomics and specific Challenge Topic, 08-AR-101 Genotyping of Existing Cohorts in Rheumatic, Skin, and Musculoskeletal Diseases. Juvenile idiopathic arthritis (JIA) is the most common autoimmune rheumatic disease of childhood and represents a series of childhood arthropathies that are largely based on clinically defined phenotypes. The two most common subtypes, and the focus of this study, are the oligoarticular and IgM rheumatoid factor negative (RF-) polyarticular forms of JIA. It is hypothesized that there are multiple genetic variants that predispose an individual to JIA and that the subtypes of JIA will differ in at least some of their susceptibility traits. Markers for these traits can be identified by systematically applying high throughput genotyping and copy number technology in a case:control genome-wide association study (GWAS) design. Phase I (GWAS I) genotyping has been completed and includes 1.8 million single nucleotide polymorphisms (SNPs) or copy number markers for 946 JIA cases and 1000 controls (Affymetrix(R) Genome-Wide Human SNP Array 6.0). Through this challenge grant opportunity, a second GWAS (GWAS-II) is proposed for 1100 additional existing JIA samples available from U.S. investigators of the Consortium on Juvenile Arthritis Genetics (CJAG) and international collaborators in Germany. Phenotypic information includes ILAR classification, age at disease onset, and joint counts. Approximately 1450 out-of-study controls are available through the GAIN study will be used for comparison in association testing for GWAS-II. This additional dataset when combined with existing complementary data from GWAS-I provides an unprecedented opportunity to reveal novel risk factors for JIA and is necessary for advancement of the field. This information may eventually lead to treatments for these disabling diseases and in the long-term contribute to preventing disability. In additional, this opportunity will contribute to a fundamental shift toward molecular definitions and reevaluation of the present criteria for defining subtypes of disease. This research proposal tests the view that juvenile idiopathic arthritis or JIA, is influenced by many genes conferring susceptibility to and protection from disease. As the genetic basis of the major autoimmune rheumatic disease of childhood becomes evident, eventually the treatment of these disabling diseases will become possible with the long term aim of preventing disability.